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Formation and elimination of glycine occur through many pathways. One precursor of glycine is choline, which can be oxidized to betaine and sequentially demethylated to dimethylglycine, sarcosine, and glycine, which is finally degraded to CO2 and NH3. Different defects in glycine metabolism lead to distinct biochemical or clinical phenotypes.



Nonketotic hyperglycinemia (NKH), also known as glycine encephalopathy (GCE), is an inherited metabolic disorder defined by deficient activity of the glycine cleavage enzyme, the main catabolic enzyme for the amino acid glycine. This results in large amounts of glycine in body fluids, often without further metabolic abnormalities. The term nonketotic hyperglycinemia reflects the history of organic acid disorders, where prior to the development of techniques to identify abnormal organic acids such as propionic acid, children who suffered from extreme acidosis and ketosis were found to have elevated plasma glycine. Subsequently, children who had increased glycine but lacked the ketosis were identified. Classic NKH is caused by mutations in protein components of the glycine cleavage enzyme. Variant NKH is caused by defects in a cofactor of the enzyme lipoic acid and encompasses a subset of the lipoate deficiency syndromes.



Two clinical variants of classic NKH are recognized: severe NKH and attenuated NKH.

Patients with severe NKH typically present as neonates or, more rarely, in the early infancy with a severe epileptic encephalopathy. Neonates appear normal at birth but develop muscular hypotonia, lethargy developing into a deep comatose state, myoclonic seizures and epileptic hiccups, and apnea within the first days of life. The hypopnea and apnea necessitate ventilator support in 85% of patients but spontaneously resolve within the first 3 weeks. The electroencephalogram (EEG) in the neonate shows a typical burst-suppression pattern, which in later infancy develops into hypsarrhythmia and multifocal epilepsy. Infants develop progressive spasticity with central hypotonia, develop therapy-resistant epilepsy, and gain no developmental skills beyond that of young infants. Orthopedic problems of scoliosis and hip problems and recurrent bronchopneumonitis are common complications in long-term survivors. Survival varies from months to decades.

An attenuated form of NKH is present in 1 of 6 affected children and is characterized by developmental progress, an absence of seizures or therapy-responsive epilepsy, and mild to absent spasticity. Half of the patients with attenuated NKH present similarly in the neonatal period, whereas others present in infancy, with those presenting after 4 months of age tending to have a better outcome. Patients with attenuated NKH make variable developmental progress, varying from a severely affected individual who only learns to sit, grasp, and communicate and who has a readily treatable epilepsy, to a patient with only mild to moderate developmental delay without epilepsy. Most patients have severe attention-deficit/hyperactivity disorder, many have ...

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